Electrode device with elongated electrode

CROSS-REFERENCES TO RELATED APPLICATIONS

0001The present patent application is a divisional of U.S. Ser. No. 13/271,720, filed Oct. 12, 2011, which is a continuation of U.S. Ser. No. 11/981,301, filed Oct. 30, 2007, now U.S. Pat. No. 8,065,021, which is a continuation of U.S. Ser. No. 10/948,516, filed Sep. 23, 2004, now U.S. Pat. No. 7,346,398, which is a continuation of U.S. Ser. No. 10/205,474, filed Jul. 24, 2002, now U.S. Pat. No. 6,907,295, which (a) claims the benefit of U.S. Provisional Application No. 60/383,157, filed May 23, 2002, which is assigned to the assignee of the present patent application and is incorporated herein by reference, and (b) is related to U.S. Ser. No. 10/205,475, filed Jul. 24, 2002, entitled, “Selective nerve fiber stimulation for treating heart conditions,” which is assigned to the assignee of the present patent application and is incorporated herein by reference.

0002This application claims the benefit of U.S. Provisional Patent Application 60/383,157 to Ayal et al., filed May 23, 2002, entitled, “Inverse recruitment for autonomic nerve systems,” which is assigned to the assignee of the present patent application and is incorporated herein by reference.

0003This application is related to a US patent application to Gross et al., filed on even date, entitled, “Selective nerve fiber stimulation for treating heart conditions,” which is assigned to the assignee of the present patent application and is incorporated herein by reference.

FIELD OF THE INVENTION

0004The present invention relates generally to electrical stimulation of tissue, and specifically to methods and devices for regulating the stimulation of nerves.

BACKGROUND OF THE INVENTION

0005As defined by Rattay, in the article, “Analysis of models for extracellular fiber stimulation,” IEEE Transactions on Biomedical Engineering, Vol. 36, no. 2, p. 676, 1989, which is incorporated herein by reference, the activation function (AF) is the second spatial derivative of the electric potential along an axon. In the region where the activation function is positive, the axon depolarizes, and in the region where the activation function is negative, the axon hyperpolarizes. If the activation function is sufficiently positive, then the depolarization will cause the axon to generate an action potential; similarly, if the activation function is sufficiently negative, then local blocking of action potentials transmission occurs. The activation function depends on the current applied, as well as the geometry of the electrodes and of the axon.

0006For a given electrode geometry, the equation governing the electrical potential is: <br />∇(σ∇<i>U</i>)=4π<i>j, </i>

0007where U is the potential, σ is the conductance tensor specifying the conductance of the various materials (electrode housing, axon, intracellular fluid, etc.), and j is a scalar function representing the current source density specifying the locations of current injection. The activation function is found by solving this partial differential equation for U. If the axon is defined to lie in the z direction, then the activation function is:

0008<maths id="MATH-US-00001" num="00001"><math overflow="scroll"><mrow><mi>AF</mi><mo>=</mo><mrow><mfrac><mrow><msup><mo>∂</mo><mn>2</mn></msup><mo>⁢</mo><mi>U</mi></mrow><mrow><mo>∂</mo><msup><mi>z</mi><mn>2</mn></msup></mrow></mfrac><mo>.</mo></mrow></mrow></math></maths><img file="US8725271B2_D0001.tif" />

0009In a simple, illustrative example of a point electrode located a distance d from the axis of an axon in a uniformly-conducting medium with conductance σ, the two equations above are solvable analytically, to yield:

0010<maths id="MATH-US-00002" num="00002"><math overflow="scroll"><mrow><mrow><mi>AF</mi><mo>=</mo><mrow><mfrac><msub><mi>I</mi><mi>el</mi></msub><mrow><mn>4</mn><mo>⁢</mo><mi>πσ</mi></mrow></mfrac><mo>·</mo><mfrac><mrow><mrow><mn>2</mn><mo>⁢</mo><msup><mi>z</mi><mn>2</mn></msup></mrow><mo>-</mo><msup><mi>d</mi><mn>2</mn></msup></mrow><msup><mrow><mo>(</mo><mrow><msup><mi>z</mi><mn>2</mn></msup><mo>+</mo><msup><mi>d</mi><mn>2</mn></msup></mrow><mo>)</mo></mrow><mn>2.5</mn></msup></mfrac></mrow></mrow><mo>,</mo></mrow></math></maths><img file="US8725271B2_D0002.tif" />

0011where I_elis the electrode current. It is seen that when σ and d are held constant, and for a constant positive I_el(to correspond to anodal current), the minimum value of the activation function is negative, and is attained at z=0, i.e., at the point on the nerve closest to the source of the anodal current. Thus, the most negative point on the activation function corresponds to the place on a nerve where hyperpolarization is maximized, namely at the point on the nerve closest to the anode.

0012Additionally, this equation predicts positive “lobes” for the activation function on either side of z=0, these positive lobes peaking in their values at a distance which is dependent on each of the other parameters in the equation. The positive values of the activation function correspond to areas of depolarization, a phenomenon typically associated with cathodic current, not anodal current. However, it has been shown that excess anodal current does indeed cause the generation of action potentials adjacent to the point on a nerve corresponding to z=0, and this phenomenon is therefore called the “virtual cathode effect.” (An analogous, but reverse phenomenon, the “virtual anode effect” exists responsive to excess cathodic stimulation.)

0013U.S. Pat. No. 6,230,061 to Hartung, which is incorporated herein by reference, describes an electrode arrangement for stimulating the heart by means of: (a) an implantable cardiac pacemaker, (b) a first electrode, coupled to a first output of the pacemaker via an intracardiac electrode line, and (c) a second electrode, for transmitting electrical stimulation pulses to the heart tissue, coupled to a second output of the pacemaker via the electrode line. The voltage pulses at the two electrodes have differing polarities relative to a third electrode. The first and second electrodes are arranged on the electrode line in such a way that the electrical dipole field which forms is distorted towards the stimulation point in such a way that a raised gradient above the stimulus threshold is formed there.

0014A number of patents and articles describe methods and devices for stimulating nerves to achieve a desired effect. Often these techniques include a design for an electrode or electrode cuff.

0015U.S. Pat. No. 4,608,985 to Crish et al. and U.S. Pat. No. 4,649,936 to Ungar et al., which are incorporated herein by reference, describe electrode cuffs for selectively blocking orthodromic action potentials passing along a nerve trunk, in a manner intended to avoid causing nerve damage.

0016PCT Patent Publication WO 01/10375 to Felsen et al., which is incorporated herein by reference, describes apparatus for modifying the electrical behavior of nervous tissue. Electrical energy is applied with an electrode to a nerve in order to selectively inhibit propagation of an action potential.

0017U.S. Pat. No. 5,755,750 to Petruska et al., which is incorporated herein by reference, describes techniques for selectively blocking different size fibers of a nerve by applying direct electric current between an anode and a cathode that is larger than the anode.

0018The following articles, which are incorporated herein by reference, may be of interest: <ul id="ul0001" list-style="none"><li id="ul0001-0001" num="0019">Ungar I J et al., “Generation of unidirectionally propagating action potentials using a monopolar electrode cuff,” Annals of Biomedical Engineering, 14:437-450 (1986)</li><li id="ul0001-0002" num="0020">Sweeney J D et al., “An asymmetric two electrode cuff for generation of unidirectionally propagated action potentials,” IEEE Transactions on Biomedical Engineering, vol. BME-33(6) (1986)</li><li id="ul0001-0003" num="0021">Sweeney J D et al., “A nerve cuff technique for selective excitation of peripheral nerve trunk regions,” IEEE Transactions on Biomedical Engineering, 37(7) (1990)</li><li id="ul0001-0004" num="0022">Naples G G et al., “A spiral nerve cuff electrode for peripheral nerve stimulation,” by IEEE Transactions on Biomedical Engineering, 35(11) (1988)</li><li id="ul0001-0005" num="0023">van den Honert C et al., “Generation of unidirectionally propagated action potentials in a peripheral nerve by brief stimuli,” Science, 206:1311-1312 (1979)</li><li id="ul0001-0006" num="0024">van den Honert C et al., “A technique for collision block of peripheral nerve: Single stimulus analysis,” MP-11, IEEE Trans. Biomed. Eng. 28:373-378 (1981)</li><li id="ul0001-0007" num="0025">van den Honert C et al., “A technique for collision block of peripheral nerve: Frequency dependence,” MP-12, IEEE Trans. Biomed. Eng. 28:379-382 (1981)</li><li id="ul0001-0008" num="0026">Rijkhoff N J et al., “Acute animal studies on the use of anodal block to reduce urethral resistance in sacral root stimulation,” IEEE Transactions on Rehabilitation Engineering, 2(2):92 (1994)</li><li id="ul0001-0009" num="0027">Mushahwar V K et al., “Muscle recruitment through electrical stimulation of the lumbo-sacral spinal cord,” IEEE Trans Rehabil Eng, 8(1):22-9 (2000)</li><li id="ul0001-0010" num="0028">Deurloo K E et al., “Transverse tripolar stimulation of peripheral nerve: a modelling study of spatial selectivity,” Med Biol Eng Comput, 36(1):66-74 (1998)</li><li id="ul0001-0011" num="0029">Tarver W B et al., “Clinical experience with a helical bipolar stimulating lead,” Pace, Vol. 15, October, Part II (1992)</li></ul>

0030In physiological muscle contraction, nerve fibers are recruited in the order of increasing size, from smaller-diameter fibers to progressively larger-diameter fibers. In contrast, artificial electrical stimulation of nerves using standard techniques recruits fibers in a larger- to smaller-diameter order, because larger-diameter fibers have a lower excitation threshold. This unnatural recruitment order causes muscle fatigue and poor force gradation. Techniques have been explored to mimic the natural order of recruitment when performing artificial stimulation of nerves to stimulate muscles.

0031Fitzpatrick et al., in “A nerve cuff design for the selective activation and blocking of myelinated nerve fibers,” Ann. Conf. of the IEEE Eng. in Medicine and Biology Soc, 13(2), 906 (1991), which is incorporated herein by reference, describe a tripolar electrode used for muscle control. The electrode includes a central cathode flanked on its opposite sides by two anodes. The central cathode generates action potentials in the motor nerve fiber by cathodic stimulation. One of the anodes produces a complete anodal block in one direction so that the action potential produced by the cathode is unidirectional. The other anode produces a selective anodal block to permit passage of the action potential in the opposite direction through selected motor nerve fibers to produce the desired muscle stimulation or suppression.

0032The following articles, which are incorporated herein by reference, may be of interest: <ul id="ul0002" list-style="none"><li id="ul0002-0001" num="0033">Rijkhoff N J et al., “Orderly recruitment of motoneurons in an acute rabbit model,” Ann. Conf. of the IEEE Eng., Medicine and Biology Soc., 20(5):2564 (1998)</li><li id="ul0002-0002" num="0034">Rijkhoff N J et al., “Selective stimulation of small diameter nerve fibers in a mixed bundle,” Proceedings of the Annual Project Meeting Sensations/Neuros and Mid-Term Review Meeting on the TMR-Network Neuros, Apr. 21-23, 1999, pp. 20-21 (1999)</li><li id="ul0002-0003" num="0035">Baratta R et al., “Orderly stimulation of skeletal muscle motor units with tripolar nerve cuff electrode,” IEEE Transactions on Biomedical Engineering, 36(8):836-43 (1989)</li></ul>

0036The following articles, which are incorporated herein by reference, describe techniques using point electrodes to selectively excite peripheral nerve fibers distant from an electrode without exciting nerve fibers close to the electrode: <ul id="ul0003" list-style="none"><li id="ul0003-0001" num="0037">Grill W M et al., “Inversion of the current-distance relationship by transient depolarization,” IEEE Trans Biomed Eng, 44(1):1-9 (1997)</li><li id="ul0003-0002" num="0038">Goodall E V et al., “Position-selective activation of peripheral nerve fibers with a cuff electrode,” IEEE Trans Biomed Eng, 43(8):851-6 (1996)</li><li id="ul0003-0003" num="0039">Veraart C et al., “Selective control of muscle activation with a multipolar nerve cuff electrode,” IEEE Trans Biomed Eng, 40(7):640-53 (1993)</li></ul>

SUMMARY OF THE INVENTION

0040It is an object of some aspects of the present invention to provide improved apparatus and methods for stimulating a nerve.

0041It is a further object of some aspects of the present invention to provide improved methods and apparatus for configuring an electrode assembly.

0042It is still a further object of some aspects of the present invention to provide improved methods and apparatus for driving an electrode assembly to apply current to a nerve.

0043In preferred embodiments of the present invention, an electrode assembly for applying current to a nerve comprises a cathode, a primary inhibiting anode and a secondary inhibiting anode, which are fixed within a housing. The cathode, near one end of the housing, is placed on or near the nerve, over a “cathodic longitudinal site” of the nerve, and is driven by a control unit to apply a cathodic current to the nerve. The primary inhibiting anode, adjacent to the cathode in the housing, is placed on or over a “primary anodal longitudinal site” of the nerve, and is driven to apply a primary anodal current to the nerve. The secondary inhibiting anode, which is separated from the cathode by the primary inhibiting anode, is placed on or over a “secondary anodal longitudinal site” of the nerve, and applies a secondary anodal current to the nerve.

0044Typically, the cathodic current applied at the cathodic longitudinal site stimulates fibers within the nerve to generate action potentials which travel in both directions within the nerve—i.e., towards the anodes (“the anodal direction”), and in the opposite direction, out of the housing, towards a target (“the target direction”). The anodal current, by contrast, is typically applied so as to inhibit the action potentials which were generated at the cathodic longitudinal site and which subsequently traveled in the anodal direction.

0045For most applications, the secondary anodal current is of lower magnitude than the primary anodal current. In this manner, the “virtual cathode” effect induced by the primary anodal current is minimized. As described in the Background section of the present patent application, the virtual cathode effect can stimulate—rather than block—the generation of action potentials in fibers in a region adjacent to the application of anodal current of a sufficiently high magnitude. In accordance with a preferred embodiment of the present invention, application of the primary and secondary anodal currents in appropriate ratios is configured to generally minimize the virtual cathode effect. Typically, but not necessarily, the ratio of the primary to the secondary anodal current ranges from 5:1 to 10:1.

0046In a preferred embodiment, a tertiary inhibiting anode is employed to reduce any virtual cathode effect which may be induced by the secondary inhibiting anode. For example, relative to a normalized cathodic current of −1, the primary inhibiting anode, secondary inhibiting anode, and tertiary inhibiting anode may be configured to apply respective currents of 0.66, 0.25, and 0.09. For some applications, the various anodes are independently driven by a control unit, so as to optimize the minimization of the virtual cathode effect and the maximization (when appropriate) of the anodally-induced hyperpolarization. Alternatively, fixed ratios are pre-defined for the currents applied by the anodes, and are set in hardware, e.g., by a set of resistors which link a single lead coming from the control unit to the respective anodes.

0047In a preferred embodiment, an elongated anode replaces the anodes described hereinabove. The elongated anode, when placed on or over a nerve, preferably has at least two levels of electrical impedance associated therewith, between respective sites on the elongated anode and the nerve. Most preferably, the portion of the elongated anode nearest the cathode has a lower level of impedance to the nerve than does another portion of the elongated anode, further from the cathode. For some applications, the variation in impedance is achieved by applying a coating (e.g., IrO2 or a more resistive material) in progressively increasing thickness to the elongated anode, beginning with a low level of the coating at the end of the elongated anode near the cathode. Alternatively or additionally, the geometry of the elongated anode is configured so as to effect the change in impedance as described. It is noted that the impedance between any site on the elongated anode and the nerve is a function not only of the properties of the anode itself, but also of the biological material which naturally permeates the region between the nerve and the anode.

0048For some applications, a primary fiber-selection anode is incorporated into the housing, adjacent to the cathode and on the other side of the housing from the primary and secondary inhibiting anodes. (Thus, the sequence of electrodes in the housing is: primary fiber-selection anode, cathode, primary inhibiting anode, secondary inhibiting anode.) The primary fiber-selection anode is preferably driven to apply anodal current of sufficient magnitude to block cathode-induced action potential propagation in some fibers, generally the larger fibers, which are more sensitive to the anodal current. If the current applied by the primary fiber-selection anode is not too high, then less-sensitive fibers, typically the smaller fibers in the nerve, are not blocked by the anodal current. Therefore, action potentials induced by the cathode continue to propagate in the smaller fibers, past the primary fiber-selection anode and out of the housing. By increasing the current driven through the primary fiber-selection anode, progressively smaller fibers are inhibited from propagating action potentials. Conversely, by decreasing the application of current through the primary fiber-selection anode, larger fibers are able to propagate action potentials, until, in the limit where the primary fiber-selection anode's current is zero, all fibers stimulated by the cathode convey their action potentials out of the housing and towards the target.

0049In a preferred embodiment, a secondary fiber-selection anode is also incorporated into the housing, adjacent to the primary fiber-selection anode and on the far side of the cathode. (Thus, the sequence of electrodes in the housing is: secondary fiber-selection anode, primary fiber-selection anode, cathode, primary inhibiting anode, secondary inhibiting anode.) In a fashion analogous to that described hereinabove with respect to the secondary inhibiting anode, the secondary fiber-selection anode is preferably driven to apply a current to the nerve smaller than that applied by the primary fiber-selection anode, so as to counteract the virtual cathode effect which would otherwise, in some circumstances, induce action potential propagation responsive to the current applied by the primary fiber-selection anode.

0050In preferred embodiments of the present invention, an electrode assembly for applying current to a nerve having a longitudinal axis comprises a housing, adapted to be placed in a vicinity of the nerve and a cathode and an anode, fixed to the housing. The cathode and anode are attached to the housing such that, when the housing is placed in the vicinity of the nerve, both the distance of the cathode and the distance of the anode to the axis are at least approximately 1.5 times greater than the radius of the nerve. By placing the cathode and anode at such a distance, increased electrical field uniformity is obtained within the nerve. In particular, the activation function (as defined in the Background section of this application) varies only relatively little across the cross-section of the nerve. This, in turn, increases the ability of a control unit driving the cathode and anode to assure that most fibers within the nerve will experience generally the same level of applied currents.

0051In preferred embodiments of the present invention, an electrode assembly is provided for applying current to a nerve having a radius and a longitudinal central axis. The electrode assembly comprises a housing, which is placed in a vicinity of the nerve, and first and second electrodes, fixed to the housing. An insulating element is fixed to the housing between the first and second electrodes so as to define a characteristic closest “insulating element distance” to the central axis that is at least approximately 1.5 times greater than the radius of the nerve. Typically, the electrodes are located at the same distance from the central axis or at a greater distance therefrom. In a preferred embodiment, the face of each electrode is located at a distance from the central axis less than or equal to the closest insulating element distance plus the width (i.e., the longitudinal extent along the nerve) of the electrode. In a preferred embodiment, the width of each electrode is approximately one half of the radius of the nerve.

0052Although many geometrical configurations are suitable for applying the principles of the present invention, the housings, electrodes, and insulating elements described herein are typically generally cylindrical, i.e., having circular cross-sections. Alternatively or additionally, at least some of these components are located at discrete locations with respect to the axis of the nerve (e.g., a single electrode located at “12 o'clock,” or four electrodes or insulating elements may be evenly distributed around the axis).

0053In preferred embodiments of the present invention, an electrode assembly for applying current to a nerve comprises a cathode and a plurality of anodes. The cathode is placed in a vicinity of a cathodic site of the nerve, and the plurality of anodes are placed in a vicinity of respective anodal longitudinal sites of the nerve. The plurality of anodes apply respective anodal currents to the nerve, that define, in combination, an anodal activation function having a depolarization portion and a hyperpolarization portion. For many applications of the present invention, the hyperpolarization portion is the “desired” portion of the anodal activation function. For example, the hyperpolarization portion may be configured to block action potential propagation in a particular direction.

0054By contrast, it is desired when performing many of these applications to minimize the depolarization portion of the anodal activation function, because the location on the nerve of the depolarization portion corresponds to the location of the virtual cathode described hereinabove. If no countermeasures would be taken, the virtual cathode could be associated with an undesired stimulation of fibers in the nerve under the virtual cathode. The virtual cathode effect could be minimized to some extent by reducing the anodal current, but, if in excess, this would result in a decrease in the magnitude of the (typically desired) hyperpolarization region. If the anodal current is only minimally reduced, in order to avoid adversely decreasing the magnitude of the hyperpolarization region, then the virtual cathode effect would typically still be present. The inventors have determined that for many electrode configurations, there is no suitable balance, i.e., either the virtual cathode effect will be reduced to a desired level, or the hyperpolarization portion of the activation function will be maintained at a sufficiently high magnitude.

0055To address this issue, the plurality of anodes provided by these embodiments of the present invention are preferably configured so as to have the maximum magnitude of the hyperpolarization portion be at least five times greater than the maximum magnitude of the depolarization amplitude. In this manner, the desired hyperpolarization effect is preserved, and the extent of depolarization due to the anodal current is minimized. Preferably, this ratio of anodally-induced hyperpolarization to depolarization is attained by using one or more of the following: (a) one or more secondary inhibiting anodes, as described hereinabove, to minimize the virtual cathode effect, (b) one or more insulating elements whose closest approach to the nerve generally remains further from the central axis of the nerve than approximately 1.5 times the radius of the nerve, or (c) electrodes, whose closest approach to the nerve generally remains further from the central axis of the nerve than approximately 1.5 times the radius of the nerve.

0056In preferred embodiments of the present invention, an electrode assembly for applying current to a nerve having a longitudinal axis, comprises two or more electrodes, adapted to be placed in a vicinity of a longitudinal site of the nerve, at respective positions around the axis. If there are only two electrodes, then the control unit preferably alternates the direction of driving a current between the two electrodes at a rate greater than 1000 Hz.

0057When there are three or more electrodes, thereby defining a ring of electrodes, the control unit preferably cycles around the electrodes in accordance with a stimulation protocol. For example, one such protocol for three electrodes may include driving current between electrodes <b>1</b> and <b>2</b>, then <b>2</b> and <b>3</b>, then <b>3</b> and <b>1</b>, then <b>1</b> and <b>2</b>, etc., cycling through the combinations at an electrode-pair transition average rate of greater than 1000 Hz, or, for some applications, greater than 10,000 Hz. For larger numbers of electrodes, e.g., 6, 12, or 24, the stimulation cycling protocol is typically more complex, and is preferably configured to cause current to pass through or close to most or all fibers in the nerve at the longitudinal site where the ring of electrodes is placed. One such complex protocol includes effectively creating a star out of the current lines passing through the nerve, or ensuring that each electrode in the ring conveys current to some, most, or all of the other electrodes.

0058Advantageously, due to the very high application rate of the current from the different electrodes compared to the relatively-low biological response rate of the fibers within the nerve, the fibers at that longitudinal site are effectively all stimulated at substantially the same time. In this manner, a single wave of action potential propagation is initiated from the longitudinal site at substantially the same time, and can be subsequently manipulated at other sites on the nerve using techniques described herein or in one or more of the patent applications cited herein that are assigned to the assignee of the present patent application and are incorporated herein by reference. Further, unlike solid ring electrodes which surround the nerve and conduct a significant portion of their current outside of the nerve, directly to the anode or cathode adjacent thereto, a larger portion of the current is conveyed into the nerve itself using the stimulation protocols described herein. From the “perspective” of the nerve, which functions at rates considerably slower than the switching rate of the ring of electrodes, it is as if a large portion of its nerve fibers were simultaneously stimulated.

0059In preferred embodiments of the present invention, an electrode assembly for applying current to a nerve having a longitudinal axis comprises a ring of two or more cathodes and a ring of two or more anodes, each ring of electrodes adapted to be placed around the nerve axis, at a respective cathodic or anodal longitudinal site of the nerve. Preferably, a control unit drives an anode in the ring of anodes to drive current through the nerve to a cathode typically at another orientation with respect to the axis, in order to stimulate fibers in the nerve nearer the cathode. Thus, for example, if each ring has twelve electrodes, then in one preferred stimulation protocol, the anode at “12 o'clock” with respect to the axis drives current generally through the nerve to the cathode at 6 o'clock. After a very short delay (typically 10-100 microseconds), the anode at 1 o'clock drives current generally through the nerve to the cathode at 7 o'clock. The pattern is preferably continued for all of the electrodes. It will be appreciated by one who has read the disclosure of the present patent application that a variety of stimulation protocols may be developed, and that a suitable protocol should typically be determined in accordance with the anatomy of the nerve, the types of nerve fibers therein, and the purpose of the stimulation, among other factors.

0060There is therefore provided, in accordance with a preferred embodiment of the present invention, apparatus for applying current to a nerve, including:

0061a cathode, adapted to be placed in a vicinity of a cathodic longitudinal site of the nerve and to apply a cathodic current to the nerve;

0062a primary inhibiting anode, adapted to be placed in a vicinity of a primary anodal longitudinal site of the nerve and to apply a primary anodal current to the nerve; and

0063a secondary inhibiting anode, adapted to be placed in a vicinity of a secondary anodal longitudinal site of the nerve and to apply a secondary anodal current to the nerve, the secondary anodal longitudinal site being closer to the primary anodal longitudinal site than to the cathodic longitudinal site.

0064In a preferred embodiment, the apparatus is adapted to be placed on the nerve such that, relative to the anodal longitudinal sites, the cathodic longitudinal site is proximal to a brain of a subject, the subject including the nerve. Alternatively, the apparatus is adapted to be placed on the nerve such that, relative to the anodal longitudinal sites, the cathodic longitudinal site is distal to a brain of a subject, the subject including the nerve.

0065In a preferred embodiment, the primary inhibiting anode is adapted to apply the primary anodal current to the nerve so as to block propagation of action potentials past the primary anodal longitudinal site.

0066For some applications, the primary inhibiting anode is adapted to apply the primary anodal current to the nerve so as to block propagation past the primary anodal longitudinal site of action potentials in a first set of nerve fibers, and to allow propagation past the primary anodal longitudinal site of action potentials in a second set of nerve fibers, the second set of nerve fibers having characteristic diameters generally smaller than characteristic diameters of the nerve fibers in the first set.

0067In a preferred embodiment, the cathode includes a plurality of cathodes, placed in the vicinity of the cathodic longitudinal site of the nerve, at respective positions around an axis of the nerve. In this case, the plurality of cathodes are preferably adapted to apply the cathodic current at a characteristic frequency greater than 1000 Hz.

0068Preferably, the apparatus includes a primary insulating element disposed between the cathode and the primary inhibiting anode. The primary insulating element is typically disposed in a position with respect to the cathode and the primary inhibiting anode so as to guide the flow of current between the cathode and the primary inhibiting anode. For some applications, the apparatus includes a secondary insulating element, disposed between the primary inhibiting anode and the secondary inhibiting anode. In this case, a characteristic size of the secondary insulating element is preferably smaller than a characteristic size of the primary insulating element. Alternatively or additionally, a characteristic distance of the secondary insulating element to an axis of the nerve is greater than a characteristic distance of the primary insulating element to the axis of the nerve.

0069In some preferred embodiments, the apparatus includes a tertiary inhibiting electrode, adapted to be placed in a vicinity of a tertiary anodal longitudinal site of the nerve and to apply a tertiary anodal current to the nerve, the tertiary anodal longitudinal site being closer to the secondary anodal longitudinal site than to the primary anodal longitudinal site. In a preferred embodiment, the tertiary inhibiting anode is configured such that a current density of the tertiary anodal current is of lower magnitude than a magnitude of a current density of the secondary anodal current.

0070Preferably, the apparatus includes a housing, coupled to the cathode, the primary inhibiting anode and the secondary inhibiting anode, adapted to facilitate placement of the cathode and the anodes in the vicinities of their respective sites. In a preferred embodiment, the housing is configured such that an arc, defined by an extent that the housing is adapted to surround the nerve, is between about 90 and 270 degrees. Alternatively, the housing is configured such that an arc, defined by an extent that the housing is adapted to surround the nerve, is between about 270 and 359 degrees.

0071Typically, a closest cathode distance to an axis of the nerve, a closest primary inhibiting anode distance to the axis, and a closest secondary inhibiting anode distance to the axis are all at least approximately 1.5 times greater than the radius of the nerve.

0072For some applications, the secondary inhibiting anode is configured such that a secondary anodal current density induced by the secondary anodal current is of lower magnitude than a magnitude of a primary anodal current density induced by the primary anodal current. In a preferred embodiment, the primary anodal current is substantially of the same magnitude as the secondary anodal current. In a preferred embodiment, a characteristic surface area of the secondary inhibiting anode is higher than a characteristic surface area of the primary inhibiting anode. For example, the characteristic surface area of the secondary inhibiting anode may be at least 2 times higher than the characteristic surface area of the primary inhibiting anode.

0073In a preferred embodiment, the secondary inhibiting anode is configured such that a current density of the secondary anodal current is of lower magnitude than a magnitude of a current density of the primary anodal current. In this case, a characteristic surface area of the primary inhibiting anode may be higher than a characteristic surface area of the secondary inhibiting anode, and a common voltage may be applied to the primary inhibiting anode and to the secondary inhibiting anode.

0074For some applications:

0075(a) the primary inhibiting anode is adapted to have associated therewith a primary level of electrical impedance between the primary inhibiting anode and the nerve, when in the vicinity of the primary anodal longitudinal site, and

0076(b) the secondary inhibiting anode is adapted to have associated therewith a secondary level of electrical impedance between the secondary inhibiting anode and the nerve when in the vicinity of the secondary anodal longitudinal site, the secondary level of impedance having a higher magnitude than the primary level of impedance.

0077In a preferred embodiment, the secondary inhibiting anode is adapted to be coupled to the housing so as to define a secondary anode distance to an axis of the nerve, and wherein the primary inhibiting anode is adapted to be coupled to the housing so as to define a primary anode distance to the axis of the nerve that is smaller than the secondary anode distance. For example, a ratio of the secondary anode distance to the primary anode distance may be greater than approximately 1.5:1.

0078In a preferred embodiment, the apparatus includes a primary fiber-selection anode, adapted to be placed in a vicinity of a primary fiber-selection anodal longitudinal site of the nerve that is closer to the cathodic longitudinal site than to the primary anodal longitudinal site. For example, the apparatus may include a secondary fiber-selection anode, adapted to be placed in a vicinity of a secondary fiber-selection anodal longitudinal site of the nerve that is closer to the primary fiber-selection anodal longitudinal site than to the cathodic longitudinal site.

0079Preferably, the apparatus includes a control unit, adapted to drive the cathode to apply the cathodic current to the nerve, adapted to drive the primary inhibiting anode to apply the primary anodal current to the nerve, and adapted to drive the secondary inhibiting anode to apply the secondary anodal current to the nerve. In one preferred embodiment, the apparatus includes a first resistive element coupled between the control unit and the primary inhibiting anode, and a second resistive element coupled between the control unit and the secondary inhibiting anode, the second resistive element having a resistance higher than a resistance of the first resistive element.

0080For some applications, the apparatus includes exactly one lead that leaves the control unit for coupling the control unit to the primary and secondary inhibiting anodes. Alternatively, the apparatus includes respective leads that leave the control unit and couple the control unit to the primary and secondary inhibiting anodes.

0081The control unit is typically adapted to configure a current density of the secondary anodal current to be of lower magnitude than a current density of the primary anodal current. In a preferred embodiment, the control unit is adapted to configure an amplitude of a current density of the cathodic current to be between 1.1 and 2 times greater than an amplitude of a current density of the primary anodal current. Alternatively or additionally, the control unit is adapted to configure an amplitude of a current density of the cathodic current to be between 3 and 6 times greater than an amplitude of a current density of the secondary anodal current. Further alternatively or additionally, the control unit is adapted to configure an amplitude of a current density of the primary anodal current to be at least 2 times greater than an amplitude of a current density of the secondary anodal current.

0082There is also provided, in accordance with a preferred embodiment of the present invention, apparatus for applying current to a nerve having a radius and a longitudinal central axis, including:

0083a housing, adapted to be placed in a vicinity of the nerve; and

0084a cathode and an anode, fixed to the housing so as to define, when the housing is placed in the vicinity of the nerve, respective closest cathode and anode distances to the axis that are both at least approximately 1.5 times greater than the radius of the nerve.

0085Preferably, the closest cathode and anode distances to the axis are both at least approximately 2 times greater than the radius of the nerve.

0086In a preferred embodiment, the cathode includes a plurality of cathodes, placed in the vicinity of the cathodic longitudinal site of the nerve, at respective positions around the axis of the nerve, each of the respective positions being at a distance from the axis at least 1.5 times greater than the radius of the nerve.

0087In a preferred embodiment, the apparatus includes an insulating element disposed between the cathode and the anode. A characteristic distance of the insulating element to the axis of the nerve is typically at least 1.5 times greater than the radius of the nerve. For some applications, the distance of the anode to the axis is substantially the same as a characteristic distance of the insulating element to the axis of the nerve. For other applications, the distance of the anode to the axis is greater than a characteristic distance of the insulating element to the axis of the nerve. For example, the distance of the anode to the axis may be within 30% of the characteristic distance of the insulating element to the axis of the nerve plus a width of the anode.

0088There is further provided, in accordance with a preferred embodiment of the present invention, apparatus for applying current to a nerve having a radius and a longitudinal central axis, including:

0089a housing, adapted to be placed in a vicinity of the nerve;

0090first and second electrodes, fixed to the housing; and

0091an insulating element, fixed to the housing between the first and second electrodes so as to define a characteristic closest insulating element distance to the central axis that is at least approximately 1.5 times greater than the radius of the nerve.

0092In a preferred embodiment, the insulating element is adapted to be placed in the vicinity of the nerve at a longitudinal site that is between respective longitudinal sites of the first and second electrodes. Alternatively, the insulating element is adapted to be placed in the vicinity of the nerve at a site with respect to the axis of the nerve that is between respective sites of the first and second electrodes, with respect to the axis.

0093There is still further provided, in accordance with a preferred embodiment of the present invention, apparatus for applying current to a nerve, including:

0094a cathode, adapted to be placed in a vicinity of a cathodic site of the nerve; and

0095a plurality of anodes, adapted to be placed in a vicinity of respective anodal longitudinal sites of the nerve and to apply respective anodal currents to the nerve, that define, in combination, an anodal activation function having: (a) a hyperpolarizing portion thereof having a maximum hyperpolarizing amplitude, and (b) a depolarizing portion thereof, having a maximum depolarizing amplitude corresponding to a depolarizing site on the nerve distal with respect to the cathode to a site corresponding to the hyperpolarizing portion, wherein the maximum hyperpolarizing amplitude is at least five times greater than the maximum depolarizing amplitude.

0096In a preferred embodiment, the apparatus includes a housing to which the cathode and the plurality of anodes are coupled, wherein a distance of a first one of the anodes to an axis of the nerve is less than a distance of a second one of the anodes to the axis, the first one of the anodes being coupled to the housing closer to the cathode than the second one of the anodes.

0097Alternatively or additionally, the apparatus includes a housing to which the cathode and the plurality of anodes are coupled, wherein a surface area of a first one of the anodes is less than a surface area of a second one of the anodes, the first one of the anodes being coupled to the housing closer to the cathode than the second one of the anodes.

0098Preferably, the apparatus includes a housing to which the cathode and the plurality of anodes are coupled, and one of the anodes is positioned within the housing so as to reduce a virtual cathode effect induced by another one of the anodes.

0099The cathode and anodes are typically disposed such that a first one of the anodal longitudinal sites is between the cathodic site and a second one of the anodal longitudinal sites. In a preferred embodiment, the anodes are disposed such that the second one of the anodal longitudinal sites is between the first one of the anodal longitudinal sites and a third one of the anodal longitudinal sites. Preferably, the anodes are adapted such that a current density of the anodal current applied at the second one of the anodal longitudinal sites has a lower magnitude than a magnitude of a current density of the anodal current applied at the first one of the anodal longitudinal sites.

0100For some applications, the anodes are adapted such that a ratio of the current density of the anodal current applied at the first site to the current density of the anodal current applied at the second site is at least 2:1. Preferably, the anodes are adapted such that a ratio of the current density of the anodal current applied at the first site to the current density of the anodal current applied at the second site is at least 5:1.

0101There is yet further provided, in accordance with a preferred embodiment of the present invention, apparatus for applying current to a nerve, including:

0102a cathode, adapted to be placed in a vicinity of a first longitudinal site of the nerve; and

0103an elongated anode, adapted to be placed in a vicinity of a second longitudinal site of the nerve, and, when so placed, to have associated therewith: (a) a first level of electrical impedance between the nerve and a location on the elongated anode proximal to the cathode, and (b) a second level of electrical impedance, greater than the first level, between the nerve and a location on the elongated anode distal to the cathode.

0104Preferably, the apparatus includes a coating disposed on a surface of the elongated anode, configured to provide the first and second levels of impedance. In a preferred embodiment, the coating is disposed on the surface in different respective thicknesses at the two locations on the elongated anode. Alternatively or additionally, the coating includes a coating that has undergone a surface treatment, and wherein the coating is configured to provide the first and second levels of impedance responsive to having undergone the surface treatment. In a preferred embodiment, the coating includes iridium oxide, titanium nitrite, and/or platinum iridium.

0105There is also provided, in accordance with a preferred embodiment of the present invention, apparatus for applying current to a nerve having a longitudinal axis, including:

0106two or more electrodes, adapted to be placed in a vicinity of a longitudinal site of the nerve, at respective positions around the axis; and

0107a control unit, adapted to:

0108(a) drive current between two of the electrodes, thereby defining a first pair of the electrodes and a first direction of current flow, and, less than one millisecond later,

0109(b) drive current between two of the electrodes, thereby defining a second pair of the electrodes and a second direction of current flow, and

0110(c) cycle between steps (a) and (b) at a rate greater than 1000 Hz,

0111wherein at least either the first pair of electrodes is different from the second pair of electrodes or the first direction of current flow is different from the second direction of current flow.

0112Typically, the two or more electrodes include three or more electrodes, or four or more electrodes.

0113For some applications, the control unit is adapted to set the rate to be greater than 4000 Hz.

0114There is yet additionally provided, in accordance with a preferred embodiment of the present invention, apparatus for applying current to a nerve having a longitudinal axis, including:

0115a set of two or more cathodes, adapted to be placed in a vicinity of a cathodic longitudinal site of the nerve, at respective positions around the axis; and

0116a set of two or more anodes, adapted to be placed in a vicinity of an anodal longitudinal site of the nerve, at respective positions around the axis.

0117As appropriate, the two or more cathodes may include six or more cathodes, e.g., twelve or more cathodes.

0118The apparatus typically includes a control unit, adapted to drive current between respective ones of the cathodes and respective ones of the anodes. The control unit is preferably adapted to cycle the current driving at a rate greater than 1000 Hz. In a preferred embodiment, the control unit is adapted to complete a sweep of driving the current through substantially all of the cathodes in less than 1000 microseconds. Preferably, the control unit is adapted to complete a sweep of driving the current through substantially all of the cathodes in less than 100 microseconds.

0119There is still additionally provided, in accordance with a preferred embodiment of the present invention, a method for applying current to a nerve, including:

0120applying cathodic current in a vicinity of a cathodic longitudinal site of the nerve;

0121applying a primary anodal current to the nerve in a vicinity of a primary anodal longitudinal site of the nerve; and

0122applying a secondary anodal current to the nerve in a vicinity of a secondary anodal longitudinal site of the nerve that is closer to the primary anodal longitudinal site than to the cathodic longitudinal site.

0123There is yet additionally provided, in accordance with a preferred embodiment of the present invention, a method for applying current to a nerve having a radius and a longitudinal central axis, including applying cathodic and anodal current to the nerve from respective cathodic and anodal current-application sites that are both located at distances from the axis of the nerve which are at least approximately 1.5 times greater than the radius of the nerve.

0124There is also provided, in accordance with a preferred embodiment of the present invention, a method for applying current to a nerve, including:

0125applying cathodic current in a vicinity of a cathodic site of the nerve; and

0126applying anodal currents in a vicinity of respective anodal longitudinal sites of the nerve, the currents defining, in combination, an anodal activation function having: (a) a hyperpolarizing portion thereof having a maximum hyperpolarizing amplitude, and (b) a depolarizing portion thereof, having a maximum depolarizing amplitude corresponding to a depolarizing site on the nerve distal, with respect to the cathodic site, to a site corresponding to the hyperpolarizing portion, wherein the maximum hyperpolarizing amplitude is at least five times greater than the maximum depolarizing amplitude.

0127There is further provided, in accordance with a preferred embodiment of the present invention, a method for applying current to a nerve having a longitudinal axis, including driving current between: (a) a set of two or more cathodic sites in a vicinity of a first longitudinal site of the nerve, which are located at respective positions around the axis, and (b) a set of two or more anodal sites in a vicinity of a second longitudinal site of the nerve, which are located at respective positions around the axis.

0128The present invention will be more fully understood from the following detailed description of the preferred embodiments thereof, taken together with the drawings, in which:

BRIEF DESCRIPTION OF THE DRAWINGS

0129<figref idref="DRAWINGS">FIG. 1A</figref> is a schematic, cross-sectional illustration of an electrode assembly for applying current to a nerve, in accordance with a preferred embodiment of the present invention;

0130<figref idref="DRAWINGS">FIG. 1B</figref> is a schematic pictorial illustration of the electrode assembly of <figref idref="DRAWINGS">FIG. 1A</figref>, in accordance with a preferred embodiment of the present invention;

0131<figref idref="DRAWINGS">FIGS. 2A and 2B</figref> are schematic, cross-sectional illustrations of other electrode assemblies for applying current to a nerve, in accordance with respective preferred embodiments of the present invention;

0132<figref idref="DRAWINGS">FIGS. 3A</figref>, <b>3</b>B, and <b>3</b>C are schematic, cross-sectional illustrations of yet other electrode assemblies for applying current to a nerve, in accordance with respective preferred embodiments of the present invention;

0133<figref idref="DRAWINGS">FIG. 4</figref> is a schematic, cross-sectional illustration of still another electrode assembly for applying current to a nerve, in accordance with a preferred embodiment of the present invention;

0134<figref idref="DRAWINGS">FIG. 5</figref> is a schematic, pictorial illustration of an additional electrode assembly for applying current to a nerve, in accordance with a preferred embodiment of the present invention;

0135<figref idref="DRAWINGS">FIG. 6</figref> is a graph modeling a calculated activation function over a range of distances from the central axis of a nerve to which current is applied using an electrode assembly such as that shown in <figref idref="DRAWINGS">FIG. 1A</figref>, in accordance with a preferred embodiment of the present invention; and

0136<figref idref="DRAWINGS">FIG. 7</figref> is a graph modeling a calculated activation function over a portion of the length of a nerve to which current is applied using an electrode assembly such as that shown in <figref idref="DRAWINGS">FIG. 2A</figref>, in accordance with a preferred embodiment of the present invention.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

0137Reference is now made to <figref idref="DRAWINGS">FIGS. 1A and 1B</figref>. <figref idref="DRAWINGS">FIG. 1A</figref> is a schematic, cross-sectional illustration of an electrode assembly <b>20</b> for applying current to a nerve <b>30</b>, in accordance with a preferred embodiment of the present invention. <figref idref="DRAWINGS">FIG. 1B</figref> is a schematic pictorial illustration of electrode assembly <b>20</b>, in accordance with a preferred embodiment of the present invention. It is noted that although the various electrode assemblies shown in the figures generally contain cylindrical configurations of their elements, other geometrical configurations, such as non-rotationally symmetric configurations, are also suitable for applying the principles of the present invention. In particular, a housing <b>22</b> of the electrode assembly (and the electrodes themselves) may form a complete circle around the nerve, or it may define an arc between approximately 0 and 90 degrees, between 90 and 180 degrees, between 180 and 350 degrees, or between 350 and 359 degrees around the nerve. (One such preferred embodiment, shown in <figref idref="DRAWINGS">FIG. 1B</figref>, includes the housing and the electrodes defining an arc of 270 degrees.)

0138Preferably, electrode assembly comprises a cathode <b>40</b>, a primary inhibiting anode <b>42</b>, and a secondary inhibiting anode <b>44</b>. Each of these electrodes is fixed within housing <b>22</b> of the electrode assembly. Insulating elements <b>24</b>, which are typically either part of the body of the housing or affixed thereto, are preferably placed so as to separate the electrodes, and to guide current from one of the electrodes towards the nerve prior to being taken up by another one of the electrodes. Preferably (as shown), the insulating elements are closer to nerve <b>30</b> than are the electrodes. Alternatively (not shown), insulating elements <b>24</b> are generally flush with the faces of the electrodes.

0139Typically, cathodic current driven through cathode <b>40</b> by a control unit (not shown) stimulates fibers within nerve <b>30</b> to generate action potentials which travel in both directions within the nerve—i.e., towards anodes <b>42</b> and <b>44</b> (“the anodal direction”), and in the opposite direction, out of housing <b>22</b>, towards a target (“the target direction”). Anodal current driven through anode <b>42</b>, by contrast, is typically applied so as to inhibit the action potentials which were induced by the cathodic current, and which subsequently traveled in the anodal direction.

0140For most applications, current applied by secondary inhibiting anode <b>44</b> is of lower magnitude than the current applied by primary inhibiting anode <b>42</b>. In this manner, the “virtual cathode” effect induced by the primary anodal current is minimized. In accordance with a preferred embodiment of the present invention, application of the primary and secondary anodal currents in appropriate ratios is configured to generally minimize the virtual cathode effect. Typically, but not necessarily, the ratio of the primary to the secondary anodal current ranges from 2:1 to 10:1.

0141<figref idref="DRAWINGS">FIG. 2A</figref> is a schematic, cross-sectional illustration of an electrode assembly <b>60</b>, in accordance with another preferred embodiment of the present invention. Electrode assembly <b>60</b> comprises a cathode <b>70</b>, a primary inhibiting anode <b>72</b>, and a secondary inhibiting anode <b>74</b>, which are typically driven in a manner analogous to that described hereinabove with respect to cathode <b>40</b> and primary and secondary inhibiting anodes <b>42</b> and <b>44</b>.

0142Preferably, electrode assembly <b>60</b> additionally comprises a tertiary anode <b>76</b>, which is employed to reduce any virtual cathode effect which may be induced by secondary inhibiting anode <b>74</b>. For example, relative to a normalized cathodic current of −1, the primary inhibiting anode, secondary inhibiting anode, and tertiary anode may be configured to apply respective currents of 0.66, 0.25, and 0.09. Typically, the magnitude of the current from the tertiary anode is sufficiently small, such that the virtual cathode effect resulting therefrom does not generate action potentials that interfere with the performance of electrode assembly <b>60</b>. For some applications, however, particularly when the current from primary inhibiting anode <b>72</b> is relatively high, additional anodes (not shown) are provided in electrode assembly <b>60</b>.

0143Electrode assembly <b>60</b> preferably comprises a primary fiber-selection anode <b>78</b>, adjacent to cathode <b>70</b> and on the other side of the housing from anodes <b>72</b>, <b>74</b>, and <b>76</b>. The current applied by cathode <b>70</b> typically induces bi-directional action potential propagation in fibers in nerve <b>30</b> having a range of diameters. In order to block propagation past anode <b>78</b> of those action potentials traveling in relatively larger fibers, the primary fiber-selection anode is preferably driven to apply anodal current configured to block action potential propagation in these larger fibers of nerve <b>30</b>, and configured not to block action potential propagation in the smaller fibers. In particular, since the larger fibers are generally more sensitive to being blocked by a lower level of anodal current than are the smaller fibers, a given level of current applied through fiber-selection anode <b>78</b> typically blocks action potentials in the larger fibers, while allowing passage of action potentials induced by the current from cathode <b>70</b> and traveling in the small fibers. Therefore, action potentials induced by the cathode continue to propagate in the smaller fibers, past primary fiber-selection anode <b>78</b>, out of housing <b>22</b>, and towards a target site. By increasing the current driven through the primary fiber-selection anode, progressively smaller fibers are inhibited from propagating action potentials. Conversely, by decreasing the application of current through primary fiber-selection anode <b>78</b>, larger fibers are able to propagate action potentials.

0144For applications in which the current applied through primary fiber-selection anode <b>78</b> is sufficient to create a substantial virtual cathode effect, a secondary fiber-selection anode <b>80</b> is preferably incorporated into electrode assembly <b>60</b>, adjacent to the primary fiber-selection anode and on the far side of cathode <b>70</b>. In a fashion analogous to that described hereinabove with respect to secondary inhibiting anode <b>74</b>, secondary fiber-selection anode <b>80</b> is preferably driven to apply a current to the nerve smaller than that applied by primary fiber-selection anode <b>78</b>, so as to counteract the virtual cathode effect which would otherwise, in some circumstances, induce action potential propagation responsive to the current applied by primary fiber-selection anode <b>78</b>.

0145Preferably, fixed ratios for the currents applied by anodes <b>72</b>, <b>74</b>, <b>76</b>, <b>78</b>, and <b>80</b> are pre-defined and are set in hardware, e.g., by a set <b>82</b> of resistors R<b>1</b>, R<b>2</b>, R<b>3</b>, R<b>4</b>, and R<b>5</b>, which couple a single lead <b>86</b> coming from a control unit <b>90</b> to the respective anodes. Typically, a guide tube <b>88</b> conveys lead <b>86</b>, in combination with a second lead <b>84</b> that drives cathode <b>70</b>, from control unit <b>90</b> to electrode assembly <b>60</b>. Advantageously, this embodiment provides control over multiple anodes, and corresponding reduction of the virtual cathode effect, with a minimum number of leads.

0146Alternatively, for some applications (not shown), particularly when cathodic and anodal current parameters vary over a wide range, the various anodes are independently driven by the control unit via respective leads, so as to optimize the minimization of the virtual cathode effect and the maximization (when appropriate) of anodally-induced hyperpolarization. For some applications, a combination of the two techniques described are utilized, whereby, for example, anodes <b>72</b>, <b>74</b>, and <b>76</b> are driven by current in a single lead, and anodes <b>78</b> and <b>80</b> are driven by current in two additional, separate leads.

0147Preferably, electrode assembly <b>60</b> (as well as the other electrode assemblies described herein, as appropriate) has physical dimensions configured so as to provide a relatively uniform activation function across the cross-section of nerve <b>30</b>. The distance L<b>1</b> separating the central longitudinal axis of nerve <b>30</b> from cathode <b>70</b> and from anodes <b>72</b>, <b>74</b>, <b>76</b>, <b>78</b>, and <b>80</b> is typically at least approximately 1.5 times greater than the radius L<b>0</b> of the nerve. For many applications, L<b>1</b> is greater than two times L<b>0</b>. By placing the cathode and anodes at such distances, increased electrical field uniformity is obtained within the nerve, particularly as the gradients in the activation function are largest near the electrodes, and are significantly reduced across the cross-section of the nerve. This, in turn, increases the ability of control unit <b>90</b> to assure that most fibers within the nerve will experience generally the same level of applied currents.

0148Insulating elements <b>24</b> preferably separate cathode <b>70</b> from anodes <b>72</b> and <b>78</b>. For some applications, additional insulating elements <b>24</b> separate the various adjacent anodes in electrode assembly <b>60</b>. The insulating elements define a characteristic closest “insulating element distance” L<b>2</b> to the axis of nerve <b>30</b> that is preferably at least approximately 1.5 times greater than L<b>0</b>. It will be appreciated that for structural reasons, spokes or other offshoots of the insulating elements may come closer to the nerve. However, the “functional” portions of the insulating elements, i.e., those portions which provide a substantial effect on the direction of current flow between the electrodes and through the nerve, preferably remain at a closest distance L<b>2</b> of at least 1.5*L<b>0</b>. For some applications, particularly those in which battery life is a pressing factor, L<b>2</b> is set to be less than 1.5*L<b>0</b>, at the expense of some uniformity of the applied field.

0149Typically, L<b>1</b> is greater than or equal to L<b>2</b>. For anode and cathode widths w, preferred values for L<b>1</b> are in the range L<b>2</b>&lt;L<b>1</b>&lt;1.5 (L<b>2</b>+w). Further preferably, L<b>2</b>+0.5w&lt;L<b>1</b>&lt;L<b>2</b>+w. Typically, the width w of the electrodes is approximately equal to 0.5*L<b>0</b>. (The width w, as well as other dimensions, are not drawn to scale in the figures.) In accordance with a preferred embodiment of the present invention, when L<b>0</b> is between 1 and 2 mm, L<b>2</b> is preferably between 1.5 and 3 mm, L<b>1</b> is between 1.5 and 4 mm, and w is between 0.5 and 1 mm.

0150<figref idref="DRAWINGS">FIG. 2B</figref> is a schematic, cross-sectional illustration of an electrode assembly <b>61</b>, in accordance with another preferred embodiment of the present invention. Electrode assembly <b>61</b> is generally similar to electrode assembly <b>60</b>, described hereinabove with reference to <figref idref="DRAWINGS">FIG. 2A</figref>, except for differences as described.

0151Whereas in electrode assembly <b>60</b>, insulating elements <b>24</b> all had generally equal dimensions, electrode assembly <b>61</b> provides each of five insulating elements <b>24</b>A, <b>24</b>B, <b>24</b>C, <b>24</b>D, and <b>24</b>E with a respective (typically different) distance to the axis of nerve <b>30</b> of L<b>2</b>(A), L<b>2</b>(B), L<b>2</b>(C), L<b>2</b>(D), and L<b>2</b>(E). In general, as the distance L<b>2</b>(<i>x</i>) for any given one of the insulating elements decreases, the current density experienced by the nerve in a vicinity of the insulating element increases. Thus, for example, in the preferred embodiment shown in <figref idref="DRAWINGS">FIG. 2B</figref>, L<b>2</b>(C) corresponding to insulating element <b>24</b>C is relatively large, such that the current density in the nerve near anode <b>76</b> is low.

0152<figref idref="DRAWINGS">FIG. 3A</figref> is a schematic, cross-sectional illustration of an electrode assembly <b>110</b>, in accordance with a preferred embodiment of the present invention. Electrode assembly <b>110</b> is analogous to electrode assembly <b>20</b>, described hereinabove with reference to <figref idref="DRAWINGS">FIG. 1A</figref>, except for differences as described. A cathode <b>120</b> of electrode assembly <b>110</b> serves generally the same purpose as cathode <b>40</b>, while an elongated anode <b>122</b> preferably replaces anodes <b>42</b> and <b>44</b>. Typically, elongated anode <b>122</b> is 0.5 mm-10 mm in length, although it may be longer or shorter responsive to the level of currents expected to be applied therethrough.

0153Elongated anode <b>122</b>, when placed on or over nerve <b>30</b>, preferably has at least two levels of electrical impedance associated therewith, between respective sites on the elongated anode and the nerve. A biological material <b>92</b>, typically including fibrous tissue and body fluids, generally occupies some of the space between the electrodes and the nerve. The impedance governing the passage of current from elongated anode <b>122</b> to nerve <b>30</b> is therefore typically a function of the properties of biological material <b>92</b>. Additionally, a resistive element <b>124</b> (e.g., a shaped iridium oxide coating, a titanium nitrite coating, or a platinum iridium coating) preferably provides greater electrical impedance distal to cathode <b>120</b> than proximal thereto. In a preferred embodiment, the coating undergoes a surface treatment (e.g., “sand blasting” or a chemical treatment), in which the effective microscopic surface area is increased by the treatment. Preferably, the proximal-to-the-cathode end of the coating is more heavily treated by the surface treatment, and therefore has lower impedance. Alternatively or additionally, the geometry of the elongated anode is configured so as to effect the change in impedance as described.

0154Typically, the anodal current leaving the portion of elongated anode <b>122</b> distal to cathode <b>120</b> minimizes the virtual cathode effect induced thereat by anodal current leaving the portion of elongated anode <b>122</b> proximal to cathode <b>120</b>.

0155<figref idref="DRAWINGS">FIG. 3B</figref> is a schematic, cross-sectional illustration of an electrode assembly <b>111</b>, in accordance with a preferred embodiment of the present invention. Preferably, a current density in a vicinity of a primary anode <b>123</b> is higher than a current density in a vicinity of a secondary anode <b>124</b>. The difference in current densities is preferably attained by having a width w<b>2</b> of anode <b>124</b> be at least 2-10 times higher than a corresponding width w<b>1</b> of anode <b>123</b>. In this manner, when generally the same current is passed through both anodes, the current density—and thus the hyperpolarizing effect on the activation function—is greater near anode <b>123</b> than near anode <b>124</b>.

0156<figref idref="DRAWINGS">FIG. 3C</figref> is a schematic, cross-sectional illustration of an electrode assembly <b>112</b>, in accordance with a preferred embodiment of the present invention. In this embodiment, the distance L<b>1</b>(B) between a primary anode <b>125</b> and the axis of nerve <b>30</b> is preferably smaller than the distance L<b>1</b>(A) between a secondary anode <b>126</b> and the axis of the nerve. The distance of cathode <b>120</b> from the axis is similar to L<b>1</b>(A) (as shown), while in other embodiments (not shown) the distance is closer to L<b>1</b>(B). In a manner similar to that described with reference to <figref idref="DRAWINGS">FIG. 3B</figref>, the geometrical configuration of the cathode and the anodes shown in <figref idref="DRAWINGS">FIG. 3C</figref> typically provides higher current density near the anode that is proximal to the cathode, and provides generally lower current density near the anode that is distal to the cathode.

0157<figref idref="DRAWINGS">FIG. 4</figref> is a schematic, cross-sectional illustration of an electrode assembly <b>140</b> surrounding nerve <b>30</b>, which is driven by a control unit <b>160</b> to apply current to the nerve, in accordance with a preferred embodiment of the present invention. Two or more electrodes <b>150</b> fixed to a housing <b>142</b> are placed at respective positions around the axis. Typically, electrodes <b>150</b> comprise at least three, and preferably four or more electrodes. In this case, insulating elements <b>144</b> are preferably disposed between adjacent electrodes. If there are only two electrodes, then control unit <b>160</b> preferably alternates the direction of the current driven between the two electrodes at a rate greater than 1000 Hz.

0158When there are three or more electrodes <b>150</b>, thereby defining a ring of electrodes, control unit <b>160</b> preferably cycles its driving of the electrodes in accordance with a stimulation protocol. For example, one such protocol for three electrodes may include driving current between electrodes <b>1</b> and <b>2</b>, then <b>2</b> and <b>3</b>, then <b>3</b> and <b>1</b>, then <b>1</b> and <b>2</b>, etc., cycling through the combinations at an average rate of greater than 1000 Hz, or, for some applications, greater than 10,000 Hz. For larger numbers of electrodes, e.g., 6, 12, or 24, the stimulation cycling protocol is typically more complex, and is preferably configured to cause current to pass through or close to most or all fibers in the nerve at the longitudinal site where the ring of electrodes is placed. One such complex protocol includes effectively creating a star out of successive current lines passing through the nerve. In <figref idref="DRAWINGS">FIG. 4</figref>, an initial set of four such lines <b>152</b>, <b>154</b>, <b>156</b>, and <b>158</b> are shown.

0159<figref idref="DRAWINGS">FIG. 5</figref> is a schematic, pictorial illustration of an electrode assembly <b>170</b>, in accordance with another preferred embodiment of the present invention. Electrode assembly <b>170</b> comprises an anodal ring <b>172</b> of two or more anodes and a cathodic ring <b>192</b> of two or more cathodes. In the preferred embodiment shown in <figref idref="DRAWINGS">FIG. 5</figref>, anodal ring <b>172</b> comprises anodes <b>174</b>, <b>176</b>, <b>178</b>, <b>180</b>, <b>182</b>, and <b>184</b>, and cathodic ring <b>192</b> comprises cathodes <b>194</b>, <b>196</b>, <b>198</b>, <b>200</b>, <b>202</b>, and <b>204</b>. Each ring of electrodes is placed around the nerve axis, at a respective anodal or cathodic longitudinal site of the nerve.

0160Preferably, a control unit drives anode <b>176</b> to drive current through nerve <b>30</b> to cathode <b>196</b>, in order to initiate generation of action potentials near cathode <b>196</b> and/or near a substantial portion of cathodic ring <b>192</b>. Cathode <b>196</b> and anode <b>176</b> are preferably at mutually-opposed orientations with respect to the axis. In this manner, a greater portion of the current from anode <b>176</b> enters nerve <b>30</b> than if, for example, the control unit were to drive anode <b>176</b> to send the same amount of charge to cathode <b>202</b>. In this latter case, a substantial portion of the current leaving anode <b>176</b> would travel directly through the biological material surrounding nerve <b>30</b>, and not enter into nerve <b>30</b>.

0161In the example shown in <figref idref="DRAWINGS">FIG. 5</figref>, after anode <b>176</b> sends current to cathode <b>196</b>, anode <b>178</b> sends current to cathode <b>198</b>, and then anode <b>180</b> sends current to cathode <b>200</b>. Preferably, an entire sweep of all of the electrodes in the two rings is accomplished within 0.01-1 millisecond.

0162Advantageously, by utilizing discrete electrodes arranged into a ring of cathodes and a ring of anodes, each located at respective longitudinal sites on the nerve, fibers in the nerve are stimulated near the ring of cathodes, and inhibited near the ring of anodes, typically using substantially less current than if a solid anode ring and a solid cathode ring were placed around the nerve. Further advantageously, steering of current to traverse or avoid certain regions in the cross-section of the nerve is readily attainable, using the techniques described herein, by suitable activation of the cathodes and/or anodes.

0163For simplicity, <figref idref="DRAWINGS">FIG. 5</figref> shows only a single anodal ring <b>172</b>. It is noted that the use of rings of anodes and/or a ring of cathodes is preferably also applied, as appropriate, in combination with the cathode—anode—anode configuration of <figref idref="DRAWINGS">FIGS. 1A and 1B</figref>, or in combination with the anode—anode—cathode—anode—anode—anode configuration of <figref idref="DRAWINGS">FIGS. 2A and 2B</figref>. In a preferred embodiment, some of the electrodes (e.g., cathode <b>70</b> and anodes <b>72</b> and <b>78</b>) comprise multiple electrodes disposed in a ring, while others of the electrodes (e.g., anodes <b>74</b>, <b>76</b>, and <b>80</b>) are generally solid rings, each comprising only a single ring.

0164<figref idref="DRAWINGS">FIG. 6</figref> is a graph modeling calculated activation function over a range of distances from the central axis of a nerve, in accordance with a preferred embodiment of the present invention. The graph models, in a simplified fashion, the activation function, at a cathodic site, produced in response to application of current by, for example, electrode assembly <b>20</b> (<figref idref="DRAWINGS">FIG. 1A</figref>) or electrode assembly <b>60</b> (<figref idref="DRAWINGS">FIG. 2A</figref>). The equation producing the graph shown in <figref idref="DRAWINGS">FIG. 6</figref> is:

0165<maths id="MATH-US-00003" num="00003"><math overflow="scroll"><mrow><mrow><mrow><mi>AF</mi><mo>⁡</mo><mrow><mo>(</mo><mi>r</mi><mo>)</mo></mrow></mrow><mo>=</mo><mrow><mfrac><mi>I</mi><mrow><mn>2</mn><mo>⁢</mo><mi>π</mi></mrow></mfrac><mo>⁢</mo><mrow><munderover><mo>∫</mo><mn>0</mn><mrow><mn>2</mn><mo>⁢</mo><mi>π</mi></mrow></munderover><mo>⁢</mo><mrow><msup><mrow><mo>[</mo><mrow><mn>1</mn><mo>+</mo><msup><mrow><mo>(</mo><mfrac><mi>r</mi><mi>R</mi></mfrac><mo>)</mo></mrow><mn>2</mn></msup><mo>-</mo><mrow><mn>2</mn><mo>⁢</mo><mrow><mo>(</mo><mfrac><mi>r</mi><mi>R</mi></mfrac><mo>)</mo></mrow><mo>⁢</mo><mi>cos</mi><mo>⁢</mo><mstyle><mspace width="0.3em" height="0.3ex" /></mstyle><mo>⁢</mo><mi>φ</mi></mrow></mrow><mo>]</mo></mrow><mrow><mo>-</mo><mn>1.5</mn></mrow></msup><mo>⁢</mo><mrow><mo>ⅆ</mo><mi>φ</mi></mrow></mrow></mrow></mrow></mrow><mo>,</mo></mrow></math></maths><img file="US8725271B2_D0003.tif" />

0166where r is the radius from the central axis of the nerve, and R is the distance of an electrode ring from the axis. L<b>0</b> in the figure shows the radius of a typical nerve, and L<b>2</b> shows the distance to an insulating element. As noted above, the amount of change of the activation function within the nerve (r<L<b>0</b>) is significantly smaller than the amount of change of the activation function outside the nerve (r>L<b>0</b>).

0167<figref idref="DRAWINGS">FIG. 7</figref> is a graph modeling calculated activation function over a portion of the length of nerve <b>30</b>, when current is applied using an electrode assembly such as that shown in <figref idref="DRAWINGS">FIG. 2A</figref> (without applying current through anodes <b>78</b> and <b>80</b>), in accordance with a preferred embodiment of the present invention. For the purposes of modeling the activation function, cathode <b>70</b> is placed at a longitudinal site on the nerve labeled z=−3 (in relative units), and anodes <b>72</b>, <b>74</b>, and <b>76</b> are placed at longitudinal positions z=0, 1.4, and 2.7. Anodes <b>72</b>, <b>74</b>, and <b>76</b> are driven to apply currents A<b>1</b>=0.66, A<b>2</b>=0.25, and A<b>3</b>=0.09, respectively. Each one of the electrodes generates its own activation function responsive to the applied currents, as modeled in <figref idref="DRAWINGS">FIG. 7</figref>.

0168The top three data lines in <figref idref="DRAWINGS">FIG. 7</figref> show that each of the anodes generates a depolarization portion (most clearly seen for applied current A<b>1</b>) and a hyperpolarization portion (clearly seen for each anode). It is noted that the depolarization portion of the activation function generated by the largest applied anodal current (A<b>1</b>) at approximately z=1.2 is substantial, and, in many cases, is sufficient to stimulate fibers within the nerve.

0169The sum of the effect of each of the anodal activation functions is seen in the fourth data line in <figref idref="DRAWINGS">FIG. 7</figref>, labeled “summed anodes.” This line demonstrates that the hyperpolarization portion of the activation function due to anodal current A<b>2</b> significantly counteracts the depolarization portion of the activation function due to anodal current A<b>1</b>. Advantageously, the peaks <b>222</b> at z>0 are generally not of sufficient magnitude to excessively stimulate the nerve fibers within nerve <b>30</b> by means of the virtual cathode effect. Nevertheless, the maximum hyperpolarization peak <b>220</b> of the “summed anodes” curve remains strong, sufficient to inhibit action potential propagation in a substantial proportion of the fibers of nerve <b>30</b>. The ratio of the magnitude of peak <b>220</b> to the magnitude of the highest of depolarization peaks <b>222</b> is typically at least 8:1, and is preferably greater than 10:1.

0170The bottom data line in <figref idref="DRAWINGS">FIG. 7</figref> shows the combined effect on the activation function due to the summed anode activation function and the activation function due to the cathode. It is noted that the use of the various anodes does not excessively decrease either the magnitude of the desired depolarizing peak <b>230</b>, or that of the desired hyperpolarizing peak <b>240</b> of the combined activation function.

0171As appropriate, techniques described herein are practiced in conjunction with methods and apparatus described in one or more of the following applications which are assigned to the assignee of the present patent application and incorporated herein by reference: <ul id="ul0004" list-style="none"><li id="ul0004-0001" num="0000"><ul id="ul0005" list-style="none"><li id="ul0005-0001" num="0172">a US patent application to Gross et al., filed on even date with the present patent application, entitled, “Selective nerve fiber stimulation for treating heart conditions,”</li><li id="ul0005-0002" num="0173">U.S. Provisional Patent Application 60/383,157 to Ayal et al., filed May 23, 2002, entitled, “Inverse recruitment for autonomic nerve systems,”</li><li id="ul0005-0003" num="0174">PCT Patent Application PCT/IL02/00068 to Cohen et al., filed Jan. 23, 2002, entitled, “Treatment of disorders by unidirectional nerve stimulation,” which published as PCT Publication WO 03/018113</li><li id="ul0005-0004" num="0175">U.S. patent application Ser. No. 09/944,913 to Cohen and Gross, filed Aug. 31, 2001, entitled, “Treatment of disorders by unidirectional nerve stimulation,” now U.S. Pat. No. 6,684,105, and</li><li id="ul0005-0005" num="0176">U.S. patent application Ser. No. 09/824,682 to Cohen and Ayal, filed Apr. 4, 2001, entitled “Method and apparatus for selective control of nerve fibers,” now U.S. Pat. No. 6,600,954.</li></ul></li></ul>

0177It will thus be appreciated by persons skilled in the art that the present invention is not limited to what has been particularly shown and described hereinabove. Rather, the scope of the present invention includes both combinations and subcombinations of the various features described hereinabove, as well as variations and modifications thereof that are not in the prior art, which would occur to persons skilled in the art upon reading the foregoing description.